ApoE, a 34-kDa protein, is the product of a single gene on chromosome 19 and exists in three major isoforms designated apoE2, apoE3 and apoE4. ApoE contains two structural domains: an amino-terminal and a carboxy-terminal domain. Each domain is associated with a specific function. The amino terminal domain contains the lipoprotein receptor binding region and the carboxy-terminal domain contains the major lipid-binding elements. The two domains appear to interact with each other in an isoform-specific manner such that amino acid substitutions in one domain influence the function of the other domain, a phenomenon referred to as domain interaction. Domain interaction is responsible for the preference of apoE4 for very low density lipoproteins (VLDL) contrasted with the preference of apoE3 for high density lipoproteins (HDL).
By redistributing lipids among the cells of different organs, apoE plays a critical role in lipid metabolism. While apoE exerts this global transport mechanism in chylomicron and VLDL metabolism, it also functions in the local transport of lipids among cells within a tissue. Cells with excess cholesterol and other lipids may release these substances to apoE-lipid complexes or to HDL containing apoE, which can transport the lipids to cells requiring them for proliferation or repair. The apoE on these lipoprotein particles mediates their interaction and uptake via the LDL receptor or the LRP.
ApoE also plays a neurobiological role. ApoE mRNA is abundant in the brain, where it is synthesized and secreted primarily by astrocytes. ApoE-containing lipoproteins are found in the cerebrospinal fluid and appear to play a major role in lipid transport in the central nervous system (CNS). ApoE plus a source of lipid promotes marked neurite extension in dorsal root ganglion cells in culture and ApoE levels dramatically increase (about 250-fold) after peripheral nerve injury. ApoE appears to participate both in the scavenging of lipids generated after axon degeneration and in the redistribution of these lipids to sprouting neurites for axon regeneration and later to Schwann cells for remyelination of the new axons. ApoE has been implicated in Alzheimer's disease and cognitive performance. ApoE4 is associated with the two characteristic neuropathologic lesions of Alzheimer's disease; extracellular neuritic plaques representing deposits of amyloid beta (Aβ) peptide and intracellular neurofibrillary tangles representing filaments of hyperphosphorylated tau, a microtubule-associated protein. ApoE4 has been associated with decreased learning ability and impaired memory. ApoE4 has been found to be a risk factor of the outcome of patients designated as having memory impairment.
Alzheimer's disease is generally divided into-three categories: early-onset familial disease (occurring before 60 years of age and linked to genes on chromosomes 21 and 14); late-onset familial disease; and sporadic late-onset disease. Both types of late-onset disease have recently been linked to chromosome 19 at the apoE locus. Other results suggest that apoE4 is directly linked to the severity of the disease in late-onset families. Recently, cholesterol lowering drugs, the statins, have been suggested for use in treating Alzheimer's disease by lowering apoE4 levels.
In the case of Alzheimer's disease alone, approximately 4 million individuals are affected in the United States. With the aging of the population, this number is projected to triple in the next twenty years. There are currently no effective therapies for arresting (and, more importantly, reversing) the impairment of central and peripheral nervous system function once an irreversible degenerative cascade begins. Likewise, there is no current therapy for restoration of normal, central and peripheral nervous system function when the induced stress has a less catastrophic or partially reversible effect compared to the dementias.
There is a need in the art for compositions and methods for treating apoE4-related disorders, such as AD and disorders related to serum lipids. The instant invention addresses this need.
Literature
Huang et al. (2001) Proc. Natl. Acad. Sci. USA 98:8838-8843; Ji et al. (2002) J. Bio. Chem. 277:21821-21828; Proc. Natl. Acad. Sci. USA 93:15051-15056; U.S. Pat. Nos. 6,046,381; 6,331,296; and 6,322,802.